Substituted 8&#39;-pyridinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a]pyrimidin-6-one and 8&#39;-pyrimidinyl-dihydrospiro-[cycloalkyl]-pyrimido[1,2-a]pyrimidin-6-one derivatives

ABSTRACT

The invention relates to a dihydrospiro-[cycloalkyl]-pyrimidone derivative represented by formula (I) or a salt thereof:  
                 
wherein X, Y, R1, R2, R3, m, n, p and q are as described herein. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

This application is a continuation of International application No.PCT/EP2004/003,051, filed Mar. 5, 2004; which claims the benefit ofpriority of European Patent Application No. 03290569.7, filed Mar. 7,2003, both of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anon-competitive inhibitor of GSK3β, enhances neuritogenesis in somemodels and also increases neuronal survival, through the induction ofsurvival factors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax. Recent studies havedemonstrated that β-amyloid increases the GSK3β activity and tau proteinphosphorylation. Moreover, this hyperphosphorylation as well as theneurotoxic effects of β-amyloid are blocked by lithium chloride and by aGSK3β antisense mRNA. These observations strongly suggest that GSK3β maybe the link between the two major pathological processes in Alzheimer'sdisease: abnormal APP (Amyloid Precursor Protein) processing and tauprotein hyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease, taupathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma.

In addition GSK3β may find application in the treatment of otherdiseases such as:

-   non-insulin dependent diabetes (such as diabetes type II) and    obesity; manic depressive illness; schizophrenia; alopecia; cancers    such as breast cancer, non-small cell lung carcinoma, thyroid    cancer, T or B-cell leukemia and several virus-induced tumors.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides dihydrospiro-[cycloalkyl]-pyrimidonederivatives represented by formula (I) or salts thereof, solvatesthereof or hydrates thereof:

wherein:

-   X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a    C₁₋₂ alkyl group and a hydrogen atom;-   Y represents a bond, a carbonyl group, a methylene group optionally    substituted by one or two groups chosen from a C₁₋₆ alkyl group, a    hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated alkyl    group or an amino group;-   R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine    ring, the ring being optionally substituted by a C₁₋₄ alkyl group, a    C₁₋₄ alkoxy group, or a halogen atom;-   R2 represents a benzene ring or a naphthalene ring; the rings being    optionally substituted by 1 to 4 substituents selected from a    C₁₋₆alkyl group, a methylenedioxy group, a halogen atom, a C₁₋₂    perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, a    hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, a    C₁₋₅ monoalkylamino group or a C₂₋₁₀ dialkylamino group;-   R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;-   m represents 1 to 4;-   n represents 0 to 3;-   p represents 0 to 2; and-   q represents 0 to 2, p+q being less than 4.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as: non-insulin dependentdiabetes (such as diabetes type II) and obesity; manic depressiveillness; schizophrenia; alopecia; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and other traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the dihydrospiro-[cycloalkyl]-pyrimidone derivatives offormula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of dihydrospiro-[cycloalkyl]-pyrimidone derivatives offormula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof; and a use of a substanceselected from the group consisting of thedihydrospiro-[cycloalkyl]-pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall of the hydrogens have been substituted by halogens, for example aCF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has been substituted by a halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

A leaving group L represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucoronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the dihydrospiro-[cycloalkyl]-pyrimidone derivativesrepresented by the aforementioned formula (I) and salts thereof, theirsolvates and hydrates also fall within the scope of the presentinvention.

The dihydrospiro-[cycloalkyl]-pyrimidone derivatives represented by theaforementioned formula (I) may have one or more asymmetric carbon atoms.As for the stereochemistry of such asymmetric carbon atoms, they mayindependently be in either (R) and (S) configuration, and the derivativemay exist as stereoisomers such as optical isomers, or diastereoisomers.Any stereoisomers in pure form, any mixtures of stereoisomers, racematesand the like fall within the scope of the present invention.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds.

One of the embodiments of the present invention includes compounds offormula (I) wherein:

-   (1) R1 represents a 3- or 4-pyridine ring and more preferably a    4-pyridine ring; or a 4- or 5-pyrimidine ring and more preferably a    4-pyrimidine ring, the rings being optionally substituted by a C₁₋₂    alkyl group, a C₁₋₂ alkoxy group or a halogen atom; and/or-   (2) R2 represents a benzene ring or a naphthalene ring, the ring    being optionally substituted 1 to 4 substituents selected from a    C₁₋₃ alkyl group, a halogen atom, a hydroxyl group or a C₁₋₂ alkoxy    group; and/or-   (3) R3 represents a hydrogen atom, a C₁₋₃ alkyl group or a halogen    atom; more preferably a hydrogen atom; and/or-   (4) Y represents a bond, a carbonyl group or a methylene group    optionally substituted by one or two groups chosen from a C₁₋₃ alkyl    group, a hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated    alkyl group or an amino group;-   (5) p+q equals 2 or 3, preferably 2; and more particularly wherein    R1, R2, R3 and Y are as defined hereinabove.

Another embodiment of the present invention include compounds of formula(I) wherein:

-   (1) R1 represents an unsubstituted 4-pyridine ring or 4-pyrimidine    ring; and/or-   (2) R2 represents a benzene ring, the ring being optionally    substituted by 1 to 4 substituents selected from a C₁₋₃ alkyl group,    a halogen atom, a hydroxyl group or a C₁₋₂ alkoxy group; and/or-   (3) R3 represents a hydrogen atom; and/or-   (4) X represents two hydrogen atoms; and/or-   (5) Y represents a bond, a carbonyl group or a methylene group    optionally substituted by a hydroxyl group; and/or-   (6) p represents 2 and q represents 0; and more particularly wherein    R1, R2, R3, X, Y, p and q are as defined hereinabove.

Particularly compounds of the present invention represented by formula(I) include compounds of table 1:

-   1.    1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   2.    1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   3.    1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   4.    1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   5.    1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   6.    1′-[2-Oxo-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   7.    1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   8.    1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   9.    1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   10.    1′-(2-Oxo-2-phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   11.    1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   12.    1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   13.    1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   14.    1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   15.    1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   16.    1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   17.    1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   18.    1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   19.    1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   20.    1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   21.    1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   22.    1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   23.    1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   24.    1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   25.    1′-(2-Hydroxy-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one-   26.    1′-(2-Oxo-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.

As a further object, the present invention concerns also methods forpreparing the dihydrospiro-[cycloalkyl]-pyrimidone compounds representedby the aforementioned formula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Dihydrospiro-[cycloalkyl]-pyrimidone compounds represented by theaforementioned formula (I), may be prepared according to the methoddescribed in the scheme 1.

In the above scheme the definition of R1, R2, R3, X, Y, m, n, p and qare the same as those already described for compound of formula (I).

Following this method, the pyrimidinone derivative represented by theabove formula (III), wherein R1, R3, m, n, p and q are as defined forcompound of formula (I), is allowed to react with a base such as sodiumhydride, sodium carbonate or potassium carbonate in a solvent such asN,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide orchloroform at a suitable temperature ranging from 0 to 130° C. undernormal atmospheric conditions, then with a compound of formula (II),wherein R2, X, Y and n are as defined for compound of formula (I) and Lrepresents a leaving group preferably bromide or mesyl group, to obtainthe compound of the aforementioned formula (I).

Alternatively compounds of formula (I) wherein Y represents a carbonylgroup may be prepared by oxidation of a compound of formula (I) whereinY represents a methylene group substituted by a hydroxyl group accordingto well known methods to one skilled in the art.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Compound of formula (III) may be prepared according to the methoddefined in scheme 2.

In the above scheme the definition of R1, R3, m, p and q are the same asalready described.

According to this method, the 3-ketoester of formula (IV), wherein R1and R3 are as defined for compound of formula (I) and R is an alkylgroup such as for example methyl or ethyl, is allowed to react with acompound of formula (V). The reaction may be carried out in the presenceof a base such as potassium carbonate, in an alcoholic solvent such asmethanol, ethanol and the like or without, at a suitable temperatureranging from 25° to 140° C. under ordinary air (i.e., normal atmosphericconditions).

Alternatively, compound of formula (III) wherein R3 represents ahydrogen atom may be halogenated in order to obtain compounds of formula(III) wherein R3 is a halogen atom such as a bromine atom or a chlorineatom. The reaction may be carried out in an acidic medium such as aceticacid or propionic acid, in the presence of bromosuccinimide orchlorosuccinimide, or bromine.

In addition, compounds of formula (III) wherein R3 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

As a further object, the present invention concerns also the compound offormula (III) as intermediate for preparing compound of formula (I).

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art. For examplecompounds of formula (IV), wherein R1 represent a pyridine ring or apyrimidine ring, optionally substituted by a C₁₋₄ alkyl group, C₁₋₄alkoxy group or a halogen atom, can be prepared by reacting respectivelyan isonicotinic acid or a pyrimidine-carboxylic acid, optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or a halogen, withthe corresponding malonic acid monoester. The reaction can be carriedout using methods well known to one skilled in the art, such as forexample in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

Compound of formula (V) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art. For examplecompound of formula (V), when m represents 1, p represents 2 and qrepresents 0, may be prepared according to the method defined in scheme3 and according to the method described by Smith and Christensen (J.Org. Chem. 1955, 20, 829) for the last step. The conditions which may beused are given in the chemical examples hereinbelow.

In the above scheme Pg represents an amino-protecting group and L aleaving group.

As another example compound of formula (V), when m equals 3, prepresents 2 and q represents 0, may be prepared according to the methoddefined in scheme 4 and according to the method described by Smith andChristensen (J. Org. Chem. 1955, 20, 829) for the last step. Theconditions which may be used are given in the chemical examples.

In the above scheme Pg represents a protecting group.

Compound of formula (VI) may be synthesized according to the methoddescribed by Bertus and Szymoniak (Chem. Commun. 2001, 1792).

Compound of formula (X) may be synthesized according to the methoddescribed by Suzuki et al. (Synthetic Communication 1998, 28(4), 701).

In the above reactions protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1 Compound No. 1 of Table 11′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(1:1) (hydrochloride) 1.1 2-(1-Amino-cyclopropyl)-ethanol hydrochloride(1:1)

To a solution of 8.63 g (45.11 mmol) of1-(2-benzyloxy-ethyl)-cyclopropylamine and 3 g of palladium 10 wt. % onactivated carbon in 100 ml of isopropanol was added 100 ml of a solutionof hydrochloric acid in isopropanol (5-6 N). The mixture was shaken at40° C. under hydrogen pressure of 4 atmospheres until hydrogen uptakeceased. The catalyst was removed by filtration and washed withisopropanol. The filtrate was evaporated to dryness to afford 6.22 g ofpure product as a viscous oil.

1.2 Tert-Butyl 1-(2-hydroxyethyl)cyclopropylcarbamate

To a solution of 6.21 g (45.11 mmol) of 2-(1-amino-cyclopropyl)-ethanolhydrochloride (1:1) in 63 ml of tetrahydrofuran were added 1 ml ofwater, 12.68 ml (90.22 mmol) of triethylamine and 9.84 g (45.11 mmol) ofdi-tert-butyl dicarbonate in 21 ml of tetrahydrofuran. The resultingmixture was stirred at room temperature for 16 h. The mixture wasevaporated, dissolved in 100 ml of diethyl ether and was treated with anaqueous hydrochloric acid solution (0.1 N). The combined extracts werewashed with saturated aqueous sodium chloride and evaporated. The crudeproduct was triturated with water and filtered to afford 6.68 g of pureproduct as a white solid. Mp: 93-95° C.

1.3 2-{1-[(Tert-butoxycarbonyl)amino]cyclopropyl}ethyl methanesulfonate

To a solution of 6.472 g (32.16 mmol) of tert-butyl1-(2-hydroxyethyl)cyclopropylcarbamate in 61 ml of anhydrousdichloromethane was added 12.79 ml (91 mmol) of anhydrous triethylamine.The resulting mixture is cooled at −20° C. Then 3.54 ml (45.66 mmol) ofmesyl chloride in 11 ml of anhydrous dichloromethane was added. Theresulting mixture was stirred at room temperature for 2 h. The mixturewas poured into ice-water and the organic layer was washed withsaturated aqueous sodium chloride, dried over sodium sulfate andevaporated. The crude product was triturated with petroleum ether andfiltered to give 7.82 g of pure product as an orange solid. Mp: 88-89°C.

1.4 Tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-cyclopropylcarbamate

To a solution of 7.82 g (28 mmol) of2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate in35 ml of anhydrous dimethylformamide was added 5.45 g (29.4 mmol) ofpotassium phthalimide. The resulting mixture was stirred at 150° C. for18 h. The mixture was then filtered and washed with diethyl ether. Thefiltrate was evaporated to dryness, the crude product was heated inwater and the precipitate was filtered. The product was dried to give4.63 g of pure compound as an orange solid. Mp: 125-127° C.

1.5 Tert-butyl 1-(2-aminoethyl)cyclopropylcarbamate

To a solution of 4.57 g (13.83 mmol) of tert-butyl1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]cyclopropylcarbamatein 80 ml of ethanol was added 3.36 ml (69.16 mmol) of hydrazine hydrateand the resulting mixture was heated under reflux for 16 h. The mixturewas filtered and washed with diethyl ether. The filtrate was evaporatedto dryness to give 2.3 g of pure compound as an orange oil.

1.6 1-(2-Aminoethyl)cyclopropanamine hydrobromide (1:2)

To a solution of 20 ml of hydrobromide (33%) in acetic acid was added2.29 g (11.46 mmol) of tert-butyl 1-(2-aminoethyl)cyclopropylcarbamateand the resulting solution was stirred at 60° C. for 1 h. The mixturewas cooled and diethyl ether was added. The resulting precipitate wasfiltered. The product was dried to give 2.69 g of pure compound as abrown solid. Mp: 233-235° C.

1.7 4,6-Diazaspiro[2.5]oct-5-en-5-amine hydrobromide (1:1)

To a solution of 2.65 g (10.11 mmol) of 1-(2-aminoethyl)cyclopropanaminehydrobromide in 21 ml of methanol was added 3.83 ml (21.24 mmol) of asolution of sodium methoxide in methanol (5.55 N). The mixture wasstirred at room temperature for 2 h. The precipitate was filtered andthe filtrate was evaporated. The crude was dissolved in 9 ml of waterand 1.07 g (10.11 mmol) of cyanogen bromide was added portion wise. Theresulting mixture was stirred at room temperature for 2 h and evaporatedto dryness to give 2.08 g of pure compound as an orange oil.

1.88′-Pyridinyl-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

A mixture of 1.77 g (9.19 mmol) of ethyl3-(pyridin-4-yl)-3-oxopropionate, 2.084 g (1-0.11 mmol) of4,6-diazaspiro[2.5]oct-5-en-5-amine hydrobromide and 2.79 g (20.22 mmol)of potassium carbonate in 17 ml of ethanol was heated at refluxtemperature during 12 h. The cooled solution was evaporated to removedsolvent, the residue was treated with water and the precipitate wasfiltered to give 0.88 g of product as a yellow powder.

Mp: 277-278° C.

1.91′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one(1:1) (hydrochloride)

To a solution of 0.5 g (1.97 mmol) of8′-pyridinyl-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-onein 10 ml of anhydrous dimethylformamide was added 0.173 g (4.33 mmol) ofsodium hydride (60% suspension in mineral oil). The mixture was allowedto stir at 50° C. for 1 h. Then 0.4 g (2.56 mmol) of(1-S)-2-chloro-1-phenyl ethanol was added and the mixture allowed tostir at 120° C. for 16 h. Water was added and the mixture extracted withethyl acetate. The extracts were washed with a saturated aqueoussolution of sodium chloride, dried and evaporated to give crude product.Purification by chromatography on silica gel eluting with a mixture ofethyl dichloromethane/methanol in the proportions 100/0 to 95/5 led tocompound in the form of free base. The base was transformed into itshydrochloride salt to give 0.443 g of pure product.

Mp: 219-221° C., [α]_(D)=−9.5 (c=0.4, CH₃OH).

¹HMR (200 MHz; DMSO-d⁶): δ 8.90 (d, 2H); 8.35 (d, 2H); 7.12-7.46 (m,5H); 6.61 (s, 1H); 4.88 (t, 1H); 3.4-4.05 (m, 4H); 1.83 (t, 2H);1.03-1.33 (m, 2H); 0.58-0.85 (m, 2H).

Example 2 Compound No. 2 of Table 11′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one(1:1) (hydrochloride)

0.31 g (0.83 mmol) of1′-[(2S)-2-hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-onewas dissolved in 8 ml of anhydrous dichloromethane and mixed with 0.145g (1.24 mmol) of N-methylmorpholine N-oxide, 0.003 g (0.0083 mmol) oftetra-n-propylammonium perruthenate and 1 g of powdered molecular sieves(4A). The mixture was stirred at 20° C. under nitrogen atmosphere for 12h. The mixture was filtered. The filtrate was washed with a saturatedaqueous solution of ammonium chloride, dried and evaporated to givecrude product. Purification by chromatography on silica gel eluting witha mixture of dichloromethane/methanol in the proportions 100/0 to 95/5gave the compound in the form of free base which was transformed intoits hydrochloride salt to give 0.078 g of pure product.

Mp: 232-234° C.

¹HMR (200 MHz; DMSO-d⁶): δ 8.62 (d, 2H); 8.03 (d, 2H); 8.00 (d, 2H);7.51-7.78 (m, 3H); 6.61 (s, 1H); 5.15 (s, 2H); 4.01 (t, 2H); 2.04 (t,2H); 1.17 (t, 2H); 0.78 (t, 2H).

Example 3 Compound No. 3 of Table 11′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(1:1)(hydrochloride) 3.1 (1-Aminocyclopentyl)acetonitrile

A solution of 15.91 g (0.15 mol) of cyclopentylideneacetonitrile in 170ml of an aqueous ammonia solution (29%) and 57 ml of methanol was heatedat 100° C. in a sealed tube for 24 h. The reaction mixture wasconcentrated, and the residue was chromatographed on silica gel elutingwith a mixture of dichloromethane/methanol in the proportions 90/10 toafford 12.15 g of the product as a colorless oil.

3.2 Tert-butyl 1-(cyanomethyl)cyclopentylcarbamate

The product was obtained by analogy with the method described in step1.2 and using (1-aminocyclopentyl)acetonitrile. The compound was used assuch in the next step.

3.3 Tert-butyl 1-(2-aminoethyl)cyclopentylcarbamate

To a suspension of 8.48 g (223.63 mmol) of lithium aluminum hydride in687 ml of diethyl ether at 0° C. was added dropwise 16.7 g (74.54 mmol)of tert-butyl 1-(cyanomethyl)cyclopentylcarbamate dissolved in 344 ml ofdiethyl ether. The resulting mixture was stirred at 0° C. under nitrogenatmosphere for 1 h. The reaction mixture was diluted with 100 ml ofdiethyl ether at 0° C. and treated with excess of a saturated aqueoussolution of sodium sulfate. Further solid sodium sulfate was added andthe organic phase was filtered to remove salts. The solvent wasevaporated to dryness to give 13.83 g of product as an oil.

3.4 1-(2-Aminoethyl)cyclopentanamine hydrobromide (1:2)

The product was obtained by analogy with the method described in step1.6 and using tert-butyl 1-(2-aminoethyl)cyclopentylcarbamate. Thecompound was used as such in the next step. Mp: 194-196° C.

3.5 6,8-Diazaspiro[4.5]dec-7-en-7amine hydrobromide (1:1)

The product was obtained by analogy with the method described in step1.7 and using 1-(2-aminoethyl)cyclopentanamine hydrobromide (1:2). Thecompound was used as such in the next step.

3.68′-Pyridinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

The product was obtained by analogy with the method described in step1.8 and using 6,8-diazaspiro[4.5]dec-7-en-7amine hydrobromide (1:1). Thecompound was used as such in the next step. Mp: 241-243° C.

3.71′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(1:1)(hydrochloride)

The product was obtained by analogy with the method described in step1.9 and using8′-pyridinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]-pyrimidin]-6′(1′H)-one.

Mp: 221-223° C., [α]_(D)=−32.8 (c=1.036, CH₃OH).

¹HMR (200 MHz; DMSO-d⁶): δ 8.91 (d, 2H); 8.41 (d, 2H); 7.13-7.47 (m,5H); 6.67 (s, 1H); 5.22 (dd, 1H); 3.71-4.04 (m, 3H); 3.38-3.59 (m, 1H);2.26-2.62 (m, 2H); 1.76-2.15 (dm, 2H); 1.30-1.76 (m, 6H).

Example 4 Compound No. 4 of Table 11′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one4.18′-Pyrimidinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one

The product was obtained by analogy with the method described in step1.8, using ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogyto the method described in patent DE 2705582) and6,8-diazaspiro[4.5]dec-7-en-7amine hydrobromide (1:1) (preparedaccording to example 3.5). The compound obtained was treated with waterand the precipitate recovered by filtration to give 2.92 g of product.Mp.: 243-244° C.

4.21′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

The product was obtained by analogy with the method described in step1.9 and using8′-pyrimidinyl-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one.

Mp: 157-158° C., [α]_(D)=−28.9 (c=1.018, CH₃OH).

¹HMR (200 MHz; DMSO-d⁶): δ9.28 (s, 1H); 9.01 (d, 1H); 8.14 (d, 1H);7.15-7.50 (m, 5H); 6.72 (s, 1H); 5.19 (t, 1H); 3.70-4.04 (m, 3H);3.38-3.58 (m, 1H); 2.26-2.55 (m, 2H); 1.74-2.12 (dm, 2H); 1.25-1.74 (m,6H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1. The compounds have been prepared according to the methods ofthe examples.

In the table, R1 is an unsubstituted pyrimidin-4-yl group or anunsubstituted pyridin-4-yl group, p represents 2, q represents 0, Phrepresents a phenyl group, (S), (R) or (Rac.) indicates in the column“Y” the stereochemistry of the carbon atom:

-   (rac.) means racemic mixture-   (R) means absolute R configuration

(S) means absolute S configuration TABLE 1

N^(o) R2 Y X R1 R3 m n Mp ° C. salt 1 Ph CH(OH) (S) H, H

H 1 0 219-221 (1:1) (hydrochloride) 2 Ph CO H, H

H 1 0 232-234 (1:1) (hydrochloride) 3 Ph CH(OH) (S) H, H

H 3 0 221-223 (1:1) (hydrochloride) 4 Ph CH(OH) (S) H, H

H 3 0 157-158 Free base 5 Ph CH(OH) (R) H, H

H 3 0 155-156 Free base 6 Ph CO H, H

H 3 0 194-196 Free base 7 Ph CO H, H

H 3 0 161-162 (1:1) (hydrochloride) 8 Ph CH(OH) (S) H, H

H 2 0 214-216 (1:1) (hydrochloride) 9 Ph CO H, H

H 2 0 242-244 (1:1) (hydrochloride) 10 Ph CO H, H

H 2 0 207-208 Free base 11 Ph CH(OH) (S) H, H

H 2 0 186-187 Free base 12 Ph CH(OH) (R) H, H

H 2 0 182-184 Free base 13 Ph CH(OH) (R) H, H

H 2 0 218-220 (1:1) (hydrochloride) 14 Ph bond H, H

H 2 0 149-150 Free base 15 Ph CH(OH) (R) H, H

H 3 0 221-222 (1:1) (hydrochloride) 16 Ph bond H, H

H 3 0 191-193 Free base 17 Ph bond H, H

H 1 0 233-235 (1:1) (hydrochloride) 18 Ph bond H, H

H 2 0 213-215 (1:1) (hydrochloride) 19 Ph bond H, H

H 3 0 227-228 (1:1) (hydrochloride) 20 Ph bond H, H

H 3 1 208-210 (1:1) (hydrochloride) 21 Ph bond H, H

H 2 1 210-211 (1:1) (hydrochloride) 22 Ph bond H, H

H 1 1 224-225 (1:1) (hydrochloride) 23 Ph bond H, H

H 2 1 166-167 Free base 24 Ph bond H, H

H 3 1 190-191 Free base 25 3-Br-Ph C(H)(OH) (Rac.) H, H

H 2 1 177-178 Free base 26 3-Br-Ph CO H, H

H 2 1 169-171 Free base

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters). In a second protocol: 4.1 μM ofprephosphorylated GS1 peptide and 42 μM ATP (containing 260,000 cpm33P-ATP) were incubated in 80 mM Mes-NaOH, pH 6.5, 1 mM Mg acetate, 0.5mM EGTA, 5 mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer for2 hours at room temperature in the presence of GSK3beta. Inhibitors weresolubilized in DMSO (final solvent concentration in the reaction medium,1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 is between 1 nanomolar to 1 micromolarconcentrations.

For example compound No. 10 of table 1 shows an IC₅₀ of 0.0006 μM.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus. Compound of Example 1 30 mg Crystallinecellulose 60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate 4mg(2) Soft capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules. Compound of Example 1 30 mg Olive oil 300 mg Lecithin 20mg(1) Parenteral preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule. Compound of Example 1 3 mgSodium chloride 4 mg Distilled water for injection 1 mlIndustrial Applicability

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A compound of formula (I) or a salt thereof, or a solvate thereof, ora hydrate thereof, or a pharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, acarbonyl group, a methylene group optionally substituted by one or twogroups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₄ alkoxygroup, a C₁₋₂ perhalogenated alkyl group or an amino group; R1represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, thering being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, or a halogen atom; R2 represents a benzene ring or a naphthalenering; the rings being optionally substituted by 1 to 4 substituentsselected from a C₁₋₆ alkyl group, a methylenedioxy group, a halogenatom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, aC₁₋₅ monoalkylamino group or a C₂₋₁₀ dialkylamino group; R3 represents ahydrogen atom, a C₁₋₆ alkyl group or a halogen atom; m represents 1 to4; n represents 0 to 3; p represents 0 to 2; and q represents 0 to 2,p+q being less than
 4. 2. The compound according to claim 1, wherein R1represents an unsubstituted 4-pyridinyl group or unsubstituted4-pyrimidinyl group.
 3. The compound according to claim 2, wherein R2represents a benzene ring, the ring being optionally substituted by 1 to4 substituents selected from a C₁₋₃ alkyl group, a halogen atom, ahydroxyl group or a C₁₋₂ alkoxy group; R3 represents a hydrogen atom; Xrepresents two hydrogen atoms; Y represents a bond, a carbonyl group ora methylene group optionally substituted by a hydroxyl group; and prepresents 2 and q represents
 0. 4. The compound according to claim 1,which is selected from the group consisting of:1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[2-Oxo-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-oneand;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Hydroxy-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;and1′-(2-Oxo-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;or a salt thereof, or a solvate thereof, or a hydrate thereof or apharmaceutically acceptable salt thereof.
 5. A compound of formula(III):

wherein: R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or5-pyrimidine ring, the ring being optionally substituted by a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, or a halogen atom; R3 represents a hydrogenatom, a C₁₋₆ alkyl group or a halogen atom; m represents 1 to 4; prepresents 0 to 2; and q represents 0 to 2, p+q being less than
 4. 6. Apharmaceutical composition comprising a compound of formula (I) or saltsthereof, or a solvate thereof, or a hydrate thereof, or apharmaceutically acceptable salt thereof according to claim 1 incombination with one or more pharmaceutically acceptable diluent,excipient or a carrier.
 7. The pharmaceutical composition according toclaim 6, wherein the compound of formula (I) is selected from the groupconsisting of:1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[2-Oxo-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-oneand;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Hydroxy-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′(H)-one;and1′-(2-Oxo-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one;or a salt thereof, or a solvate thereof, or a hydrate thereof or apharmaceutically acceptable salt thereof.
 8. A method of treating adisease in a patient caused by abnormal GSK3β activity comprisingadministering to said patient a therapeutically effective amount of acompound of formula (I) or a salt thereof, or a solvate thereof, or ahydrate thereof, or a pharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, acarbonyl group, a methylene group optionally substituted by one or twogroups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₄ alkoxygroup, a C₁₋₂ perhalogenated alkyl group or an amino group; R1represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, thering being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, or a halogen atom; R2 represents a benzene ring or a naphthalenering; the rings being optionally substituted by 1 to 4 substituentsselected from a C₁₋₆ alkyl group, a methylenedioxy group, a halogenatom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, aC₁₋₅ monoalkylamino group or a C₂₋₁₀ dialkylamino group; R3 represents ahydrogen atom, a C₁₋₆ alkyl group or a halogen atom; m represents 1 to4; n represents 0 to 3; p represents 0 to 2; and q represents 0 to 2,p+q being less than
 4. 9. The method according to claim 8, wherein R1represents an unsubstituted 4-pyridinyl group or unsubstituted4-pyrimidinyl group.
 10. The method according to claim 9, wherein R2represents a benzene ring, the ring being optionally substituted by 1 to4 substituents selected from a C₁₋₃ alkyl group, a halogen atom, ahydroxyl group or a C₁₋₂ alkoxy group; R3 represents a hydrogen atom; Xrepresents two hydrogen atoms; Y represents a bond, a carbonyl group ora methylene group optionally substituted by a hydroxyl group; and prepresents 2 and q represents
 0. 11. The method according to claim 8,wherein the compound of formula (I) is selected from the groupconsisting of:1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[2-Oxo-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Oxo-2-phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2S)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-[(2R)-2-Hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylmethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(phenylethyl)-8′-pyridin-4-yl-3′,4′-dihydrospiro-[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′-one;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-oneand;1′-(phenylethyl)-8′-pyrimidin-4-yl-3′,4′-dihydrospiro-[cyclopentane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;1′-(2-Hydroxy-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;and1′-(2-Oxo-2-(3-bromo-phenylethyl))-8′-pyrimidin-4-yl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;or a salt thereof, or a solvate thereof, or a hydrate thereof or apharmaceutically acceptable salt thereof.
 12. The method according toclaim 8, wherein the disease is a neurodegenerative disease.
 13. Themethod according to claim 12, wherein the neurodegenerative disease isselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, taupathies, vascular dementia; acute stroke, traumaticinjuries; cerebrovascular accidents, brain cord trauma, spinal cordtrauma; peripheral neuropathies; retinopathies or glaucoma.
 14. Themethod according to claim 13, wherein the disease is Alzheimer'sdisease.
 15. The method according to claim 13, wherein the disease isParkinson's disease.
 16. The method according to claim 13, wherein thedisease is taupathies.
 17. The method according to claim 13, wherein thedisease is vascular dementia.
 18. The method according to claim 13,wherein the disease is stroke, traumatic injuries or cerebrovascularaccidents.
 19. The method according to claim 8, wherein the disease isselected from the group consisting of non-insulin dependent diabetes;obesity; manic depressive illness; schizophrenia; alopecia; and cancers.20. The method according to claim 19, wherein the cancer is breastcancer, non-small cell lung carcinoma, thyroid cancer, T or B-cellleukemia or virus-induced tumors.